Clinical Considerations for Uterine Serous Cancer

Abstract & Commentary

By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston. Dr. Coleman reports no financial relationships relevant to this field of study.

This article originally appeared in the December 2012 issue of OB/GYN Clinical Alert.

Synopsis: Uterine (papillary) serous cancer is a genomically unstable cancer associated with poor survival even in stage i. it is also frequently associated with a secondary malignancy, particularly breast cancer. Comprehensive surgical staging is recommended since extrauterine disease can be present without other high-risk uterine features, like myometrial invasion. However, an optimal adjuvant treatment protocol remains to be defined.

To evaluate the impact of surgical staging on survival of women with early stage (Stage IA and Stage IB) uterine papillary serous cancer (USC), a retrospective analysis was undertaken on patients treated over a 15-year period at two institutions. Over this time period, 84 cases of early stage cancer were identified. The diagnosis was based on histologic features, including papillary architecture with tuft stratification, marked nuclear pleomorphism, high nuclear-to-cytoplasmic ratio, and a high mitotic count. Of the 84 identified cases, the majority were stage IA (n = 71); 37 patients (44%) had a history of a second cancer (22 breast tumors, 9 synchronous müllerian cancers). Surgical staging with at least hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and bilateral pelvic lymph node dissection was performed in 60 (71%) of 84 patients. The median survival for all patients was 10 years. univariate analysis revealed that surgical staging (P < 0.001), normal preoperative CA-125 (P < 0.001), and absence of a secondary malignancy (P < 0.01) were associated with improved survival. Age-adjusted multivariate analysis incorporating these factors revealed that surgical staging (hazard ratio, 0.18; P < 0.001), substage (hazard ratio, 4.59; P < 0.05), and history of a second malignancy (hazard ratio, 2.75; P < 0.04) were independent factors associated with reduced overall survival. The former two remained independent factors if secondary malignancy was excluded. Treatment approach (observation, radiation, chemotherapy, or both) did not impact survival. It was concluded that independent of adjuvant therapy, early substage of disease, comprehensive surgical staging, and the presence of a second malignancy significantly impacted overall survival.

Commentary

Uterine papillary serous, now termed uterine serous cancer, is widely recognized as unique histology, distinguished from “common” type or endometrioid adenocarcinoma by its frequent metastatic disease at presentation, frequent recurrence, and poor overall survival. Classically, it has underscored the two-class nomenclature frequently seen in textbooks, which highlight a disease (type II) that is associated with older age at presentation, absence of obesity, disassociation from estrogen use, and deep myometrial invastion.1 USC accounts for just 10% of all primary uterine cancers but is responsible for 40% of the cancer-related deaths. The rarity of presentation has hindered clear treatment guidelines, particularly from Phase 3 adjuvant trials. This has led to a series of reports, like the current, which are retrospective in nature, generally with small patient cohorts, and gathered over long periods of time. However, from these types of studies, hypotheses can be generated which, until better information is available, can help foster rational treatment approaches. For most gynecologic oncologists, the most significant is recognition that uterine factors, such as size, location, and depth of myometrial invasion, are poorly associated with the probability of extrauterine spread. This is common practice for endometrioid, particularly early-stage, low-grade tumors where the risk of extrauterine spread is < 5% and formal staging may be overtreatment and unnecessary. In USC, even tumors confined to a polyp are associated with extrauterine or peritoneal dissemination (particularly the omentum) in one-third of patients.2 The Society of Gynecologic Oncology and the National Comprehensive Cancer Network both have issued guidelines recommending surgical staging in all such cases if medically feasible.

The high rate of secondary tumors, particularly breast cancer, is curious but consistent across USC studies. The Cancer Genome Atlas (TCGA) has characterized USC to be not only distinct from its endometrioid counterpart, but in many ways, similar to high-grade serous ovarian cancer, with frequent P53 mutation and E-cadherin loss. The relationship between breast and ovarian cancer is well documented, but the association of BRCA germline mutation carrier status and USC is much less clear. Although more investigation is needed, the frequency of USC and breast cancer does raise the question of hysterectomy at the time of risk-reducing ovarian/tubal surgery for high-risk individuals.

In all, the USC population represents an important and distinct entity of disease challenged by much of the same clinicopathological features seen in ovarian malignancy. It is hoped that information emerging from the TCGA and other genomic interrogation efforts will help identify novel targets for future intervention.3